“bath salts:” cathinones and related toxicology lauren richards-waugh, ph.d. marshall university...
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“Bath Salts:” Cathinones and Related Toxicology
Lauren Richards-Waugh, Ph.D.Marshall University
Forensic Science Graduate Program
Outline
• Description of the problem• Classification of widely abused synthetic
cathinones• Methylone, mephedrone, and 3,4-
methylenedioxypyrovalerone (MDPV)– Pharmacology – Case reports
• Second generation compounds• Alpha-pyrrolidinopentiophenone (α-PVP)– Pharmacology – Case Reports
Cathinone
• Pharmacologically active, natural component of the khat plant (Catha edulis)
• Chewing of the leaves for stimulant properties has a long history
• Dried leaves are not as stimulating • Naturally converted to cathine (much less active)
Initial Good Intentions
• Methcathinone and mephedrone were first synthesized in the late 1920s
• Prescribed as antidepressants
• Medical use was not long term– Serious side effects
• Had a revival in the mid-2000s–Many more have been synthesized
How did we get here?• 2004 – move toward combing pharmaceutical literature for
novel compounds
• Production moves from clandestine labs to international industrial chemical suppliers
• Internet marketing and sales
• Began with 1-benzylpiperidines (BZP)
• Currently, cathinones , cannabinoids, tryptamines, NBOMe compounds
Most Commonly Reported Desirable Effects
• Increased alertness• Analgesic effects• Increased energy• Stimulation• Increased libido• Euphoria• Empathy
Synthetic Cathinones• Often described as a “legal” alternative to cocaine or
amphetamine• “Designer” drugs – structurally similar to existing drugs• Contained within products marketed as bath salts,
bonsai food, powder cleaner and many others– Labeled “not for human consumption”
US Poison Control Centers:Calls regarding human Exposures to Bath Salts
https://aapcc.s3.amazonaws.com/files/library/Bath_Salts_Data_for_Website_10.31.2013.pdf – accessed Nov. 22, 2013
2010 2011 2012 2013 (as of 10/31)
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
304
6138
2691
833
MDPV Timeline• Around 2005 – Online discussions of MDPV began– Tracked by The Psychonaut Web Mapping Project
• 2008 through 2009 – escalating number of user accounts reported online
• 2010 – first “bath salt” exposure reported to a U.S. Poison Control Center
• “Bath salts” cases began to flood the U.S. news media in early 2011
Classification of Synthetic Cathinones
Phenethylamines α-methylatedphenethylamines
Methylenedioxy-phenethylamines
Ring substitutedmethylenedioxy-phenethylamines
β-ketonatedmethylenedioxy-phenethylamines
Ring substitutedamphetamines
β-ketonatedamphetamines
Cathinone Substitutedcathinones
PyrrolidineDerivatives
Most frequently abused synthetic cathinones
• United States– 3,4-methylenedioxypyrovalerone (MDPV)• Substance most commonly detected in blood and urine in
patients hospitalized for bath salts overdose in the US
– 3,4-methylenendioxymethcathinone (methylone)
• Europe– 4-methylmethcathinone (mephedrone)– Replacing MDMA in “ecstasy” tablets
Structural Similarities
Amphetamine MDMA
Pyrovalerone Methylone Mephedrone
MDPV
PhenethylamineDopamine
Predicted Pharmacology of Synthetic Cathinones
• Structural similarities to compounds with known pharmacology– MDMA, amphetamines, dopamine
• Increases the amount of extracellular monoamine neurotransmitters– Dopamine (DA), Norepinephrine (NE), Serotonin (5-HT)– Abbreviations for respective transporters = DAT, NET and SERT
• Mechanisms leading to increased extracellular neurotransmitters– Stimulate release and Inhibit reuptake
• Small number of studies evaluating pharmacology, toxicology, and physiology
Mechanism of Action: Mephedrone, Methylone and MDPV
• In vitro studies performed using rat brain synaptosomes – IC50 for DAT, NET and SERT uptake measured
• Uptake of all three neurotransmitters blocked by methylone and mephedrone
• MDPV blocks DAT and NET uptake, but not SERT
– EC50 determined for release of DAT, NET and SERT• Mephedrone and methylone stimulate release at all three
transporters• MDPV is inactive as a releaser
Synthetic Cathinones Administered to Rodents
• Lack of scientific literature describing pharmacology and toxicology until very recently
• Compounds introduced to market faster than studies can be performed
• Several studies performed since 2012– Marusich et al., NeuroToxicology. 2012– Aarde et al., Neuropharmacology. 2013– Baumann et al., Neuropsychopharmacology. 2013– Fentegrossi et al., Neuropharmacology 2013– Cameron et al., Psychopharmacology. 2013
Summary of MDPV Effects in Rodents
• Self administration• Increased dopamine release• Increased locomotor activity– Time and dose dependent
• Tachycardia• Hypertension• Effects and behaviors dependent on temperature– Stereotypy, self injury, hyperthermia
Sympathomimetic/Stimulant Toxidrome
Signs and Symptoms– Excessive speech– Excessive motor activity– Tremor– Insomnia– Anorexia– Hyperreflexia– Seizures– Rhabdomyolysis
Causative Agents– Amphetamines– Methamphetamine– Caffeine– Cocaine– Ephedrine– LSD– Methylphenidate– Nicotine– PCP– Salbutamol– Phenylpropanolamine
Toxidrome = recognizable syndromes related to drug toxicity
– Tachycardia– Hyperactive bowel sounds– Diaphoresis– Anxiety– Delusions– Mydriasis– Paranoia– Piloerection
Symptoms Reported in Cases of Synthetic Cathinone Intoxication
Sympathomimetic, cardiovascular, CNS and neuropsychiatric effects
Leading Causes of Death in Cases Involving Synthetic Cathinones
1. Acute drug toxicity– Decedent has usually ingested multiple drugs
2. Self harm and at risk behavior – Hanging– Self-inflicted gunshot wounds– Self-mutilation (lacerations)– Jumping from tall structures– Slitting one’s own throat
MDPV Case Series Overview• 11 Fatalities investigated at the West Virginia Office of the Chief
Medical Examiner (WV OCME)• Timeline: March 2011 and November 2011– 6 Accidental (Drug Related)• 5 were positive for other drugs in addition to MDPV
– 3 Accidental (Non-drug Related)• 1 motor vehicle accident• 2 accidental drownings
– 1 Suicide• Hanging
– 1 Homicide• Gun shot wound (inflicted by law enforcement)
Accidental Drug Overdoses
• Male, 47 y, COD = Fatal excited delirium due to MDPV intoxication
• Female, 51 y, COD = Hypoxic encephalopathy due to fatal excited delirium due to presumed MDPV intoxication
• Male, 28, COD = Combined MDPV, duloxetine, and lithium intoxication– Evidence of self mutilation– Previous suicide attempts– Capsules and journal discovered on death scene
Synthetic Cathinones Banned in the US
• October 21, 2011 – mephedrone, methylone, MDPV as well as their salts, isomers, and isomers of salts temporarily placed onto Schedule 1 of the Controlled Substances Act (CSA)
• June 2012 – Synthetic Drug Abuse Prevention Act was passed– Mephedrone and MDPV added to Schedule 1 of CSA
• October 2012 – Mephedrone scheduling extended until April 20, 2013
New Synthetic Stimulants Reported in Forensic Casework
• Marinetti and Antonides, JAT 2013– Most recently –α-pyrrolidonpentiophenone (α-PVP) and Pentylone– Others detected – Methylone, Pyrovalerone and Methedrone
• Shanks et al., JAT 2012– Report MPPP, α-PVP and Butylone detected in products analyzed
between September 8, 2011 and April 1, 2012 (“Post- federal ban”)
• WV OCME– α-PVP detected in several postmortem cases– Pentedrone also detected in one case
Alpha-PVP –similarities to other well-studied compounds
• MDPV and pyrovalerone– Pyrrolidine derivative compounds tend to lack entactogenic
effects– Pyrovalerone causes the releases of dopamine and
norepinephrine from respective nerve terminals
• Structural analogs of pyrovalerone have been shown to inhibit monoamine transporters including dopamine, serotonin and norepinephrine
α-PVPMDPV Pyrovalerone
α-PVP Case Series• Six fatalities investigated at the WV OCME between
March and December 2012• Many more clues in α-PVP cases than MDPV cases
– Evidence submitted in one case
• All three vials contained α-PVP and pentedrone• Vial “SF” also contained N-ethylcathinone, 4-methyl-
N-ethylcathinone, butylone, and 3',4'-methylenedioxy-α-pyrrolidinobutiophenone (MDPBP)
January 28, 2014 – DEA Notice of Intent to Schedule
(1) 4-methyl-N-ethylcathinone (4-MEC)
(2) 4-methylalpha-pyrrolidinopropiophenone (4-MePPP)
(3) alphapyrrolidinopentiophenone (α-PVP)
(4) 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone)
(5) 2-(methylamino)-1-phenylpentan-1-one (pentedrone)
(6) 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1-one (pentylone)
(7) 4-fluoro-Nmethylcathinone (4-FMC)
(8) 3-fluoro-N-methylcathinone (3-FMC)
(9) 1-(naphthalen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one (naphyrone)
(10) alpha-pyrrolidinobutiophenone (α-PBP)
A Few Compounds Advertised in Products Currently for Sale
• 3',4'-Methylenedioxy-a-pyrrolidinobutyrophenone (MDPBP) • α-pyrrolidinopentiophenone (α-PVP)
α-PVPMDPBP Buphedrone
Naphyrone Methiopropamine Pentedrone
Summary and Conclusions• In general, synthetic cathinones cause an increase in the
extracellular concentrations of the neurotransmitters DA, NE and/or 5-HT
• Symptoms of synthetic cathinone intoxication include sympathomimetic, cardiovascular and CNS overstimulation as well neuropsychiatric effects
• Manufacturers of bath salts products quickly adjust to legislation to change the composition of their products– Results in limited knowledge regarding pharmacology and toxicology
of newer compounds
• Due to structural similarities, many synthetic cathinones (will
likely) have similar pharmacology and toxicology
Full References for Studies Listed During Presentation
• Aarde, S. M., P. K. Huang, K. M. Creehan, T. J. Dickerson and M. A. Taffe (2013). "The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats." Neuropharmacology 71: 130-140.
• Baumann, M. H., J. S. Partilla and K. R. Lehner (2013). "Psychoactive "bath salts": not so soothing." Eur J Pharmacol 698(1-3): 1-5.
• Baumann, M. H., J. S. Partilla, K. R. Lehner, E. B. Thorndike, A. F. Hoffman, M. Holy, R. B. Rothman, S. R. Goldberg, C. R. Lupica, H. H. Sitte, S. D. Brandt, S. R. Tella, N. V. Cozzi and C. W. Schindler (2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products." Neuropsychopharmacology 38(4): 552-562.
• Cameron, K., R. Kolanos, R. Verkariya, L. De Felice and R. A. Glennon (2013). "Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of "bath salts," produce opposite effects at the human dopamine transporter." Psychopharmacology (Berl) 227(3): 493-499.
• Fantegrossi, W. E., B. M. Gannon, S. M. Zimmerman and K. C. Rice (2013). "In vivo effects of abused 'bath salt' constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice: drug discrimination, thermoregulation, and locomotor activity." Neuropsychopharmacology 38(4): 563-573.
• Marinetti, L. J. and H. M. Antonides (2013). "Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results." J Anal Toxicol 37(3): 135-146.
• Marusich, J. A., K. R. Grant, B. E. Blough and J. L. Wiley (2012). "Effects of synthetic cathinones contained in "bath salts" on motor behavior and a functional observational battery in mice." Neurotoxicology 33(5): 1305-1313.
• Shanks, K. G., T. Dahn, G. Behonick and A. Terrell (2012). "Analysis of first and second generation legal highs for synthetic cannabinoids and synthetic stimulants by ultra-performance liquid chromatography and time of flight mass spectrometry." J Anal Toxicol 36(6): 360-371.